Retlirafusp alfa (SHR-1701), a bifunctional programmed death-ligand 1 (PD-L1) antibody fused to a TGF-β trap, was approved in China on January 7, 2026 for first-line treatment of PD-L1-positive advanced gastric or gastroesophageal junction adenocarcinoma with chemotherapy. This first-in-class milestone revisits a key question raised by bintrafusp alfa (M7824): why can dual PD-L1/TGF-β targeting be active in selected settings yet inconsistent across tumors? We highlight that TGF-β-driven immune suppression and immune exclusion are often spatially organized within stromal niches, vary across indications, and are not always the dominant barrier even when PD-L1 is expressed. SHR-1701’s approval provides proof of principle in a defined context and supports mechanism-aligned development using biomarker-driven selection, rational combinations and sequencing, and pharmacodynamic endpoints that directly test these assumptions.

This paper established a Susceptible-Infected-Recovered-Dead (SIRD) model to fit and predict the COVID-19 epidemic in China. On the premise of passing the Markov Chain Monte Carlo (MCMC) robustness check, we counterfactually assessed the effectiveness of partial unlocking and vaccination policies. Our key findings are as follows: (1) The SIRD model predicted that China could fully contain COVID-19 in July, 2020, which is consistent with reality; (2) If the strict social distancing policies are relaxed before the epidemic ends, it will lead to a second rebound. Even worse, the rebound increases with the advance of relaxation time and relaxation degree; (3) Timely vaccination is the best strategy if it is available. However, delayed vaccination is much less effective. (4) When further taking natural population growth rates into account, we find that the principal conclusions remain robust. The inclusion of demographic dynamics helps mitigate potential fitting bias resulting from changes in population size over extended epidemic periods like the COVID-19 pandemic. Empirically, the model shows a certain degree of applicability in regions with similar transmission trends. This paper theoretically and quantitatively supports the view that the effectiveness of China’s comprehensive prevention and control measures, and empirically verifies that the model has potential reference significance for some regions with similar transmission trends.

Antibodies targeting TGF-β and PD-L1 initially showed promise as second-generation PD-L1 agents. However, consecutive trial failures have limited their clinical success. Our study reveals that the efficacy of the TGF-β×PD-L1 bispecific antibody (BsAb) is compromised by insufficient activation of innate immune responses. To address this, we combine STING agonists with the BsAb, significantly enhancing tumor suppression beyond that achieved with standard STING agonist plus anti-PD-L1 combinations in preclinical models. Unexpectedly, even STING agonist monotherapy is improved by TGF-β blockade, suggesting that TGF-β suppresses STING-driven immune activation. We find that this synergy is mediated by the CXCL16-CXCR6 axis, where STING activation and TGF-β blockade promote CXCL16 expression in macrophages and dendritic cells, recruiting and sustaining cytotoxic CXCR6+ T cells. Additionally, PD-L1 blockade further enhances their antitumor activity. To optimize this strategy, we develop Y101S, an antibody-drug conjugate targeting TGF-β, PD-L1, and STING, which demonstrates superior tumor control and immune modulation in preclinical models. These findings highlight the therapeutic potential of this triple-targeting approach.

Since its discovery, the cyclic GMP-AMP synthase (cGAS)-stimulator of the interferon gene (STING) signaling pathway has been considered a pivotal component of innate immunity and a promising target for cancer immunotherapy. Beyond its canonical role in pathogen defense, accumulating evidence has demonstrated that the cGAS-STING pathway critically regulates diverse cellular processes, including cellular senescence, autophagy, cell death, and tumor immunosurveillance; therefore, dysregulation of this pathway correlates with the pathogenesis and progression of various human diseases, ranging from autoimmune and inflammatory disorders to cancer. Herein, we reviewed the regulatory mechanisms and cellular functions of the cGAS-STING pathway, highlighting its essential role in maintaining immune homeostasis. We systematically discussed the dual roles of the cGAS-STING pathway in cancer immunity, in which it triggers both antitumor and immunosuppressive effects. Finally, we summarized the recent advances and challenges in therapeutic strategies targeting the cGAS-STING pathway and discussed the next generation of therapies, including nanomaterials, antibody-drug conjugates, engineered bacteria, alternative strategies, optogenetic approaches, and combination strategies. We hope that our efforts will advance the understanding of the fundamental principles of innate immune recognition and response, and provide novel directions for improving the clinical outcomes of cGAS-STING-targeted therapies.

Gynecological cancer poses a serious threat to women's health. Despite significant advances in immunotherapy and targeted therapeutic strategies for gynecological cancers, substantial challenges persist, including limited response rates, inevitable resistance, and adverse effects. In recent years, a milestone in gynecological cancer therapy has been the approval of antibody-drug conjugates (ADCs). In this review, we provide a comprehensive overview of the structural features, mechanisms of action, and molecular characteristics of ADCs that have been approved and are currently under development. Their clinical applications and associated challenges have also been highlighted. Finally, we discuss the prospects of ADCs in the treatment of gynecological cancers.

BACKGROUND:The incidence of breast cancer remains high and it remains the leading cause of cancer-related deaths in women. A better understanding of the molecular mechanisms of breast cancer and identifying novel biomarkers will help improve therapeutic strategies. Citrate lyase beta like (CLYBL) is expressed at low levels in breast cancer tissues and is associated with low patient survival rates. In this study, we explored the regulatory mechanisms of CLYBL and its acetylation in breast cancer. METHODS:CLYBL expression patterns in breast cancer were assessed using a breast cancer tissue microarray, immunohistochemistry, and publicly available datasets. The acetylation patterns of CLYBL and the related regulatory functions were detected by high resolution mass spectrometry, immunoprecipitation assays, and western blot analysis. The potential effects of CLYBL and its acetylation on breast cancer were determined using both in vitro and in vivo assays. RESULTS:CLYBL was expressed at lower levels in breast cancer samples compared with normal tissues. This low CLYBL expression was associated with poor patient survival rates. Overexpressing CLYBL could inhibit breast cancer and reduce NRF2 pathway-mediated antioxidants. We identified two acetylated lysine sites in CLYBL, K57 and K82, using acetylated peptide affinity enrichment and high-resolution mass spectrometry. Our results suggest that K82 is the main acetylation site. Further work showed that the p300/CBP associated factor (PCAF) and histone deacetylase 3 (HDAC3) as the CLYBL acetyltransferase and deacetylase, respectively. Additionally, CLYBL acetylation facilitates its own protein stability by reducing it affinity for ubiquitin, thus enhancing the anti-breast cancer effects. CONCLUSION:We revealed the role of CLYBL overexpression and its acetylation in breast cancer. Our study suggests that CLYBL is a potential molecular target for breast cancer therapy.

Cancer immunotherapy has emerged as one of the most groundbreaking advancements. However, the tumor microenvironment (TME) is often dominated by various immunosuppressive factors, compromising the efficacy of single-target therapies, leading to non-responsiveness or resistance. Bispecific antibodies (BsAbs) represent an innovative immunotherapeutic strategy with enormous potential for improving cancer treatment outcomes. Unlike monoclonal antibodies, BsAbs can concurrently inhibit multiple pro-tumor pathways, target immune checkpoints to mitigate resistance, and bind to two distinct antigens, thereby enhancing specificity while minimizing off-target effects. Moreover, BsAbs are more cost-efficient and less toxic compared to the use of two separate monoclonal antibodies in combination. In recent decades, BsAbs have made remarkable progress in clinical development. Several BsAbs, such as Blinatumomab, Mosunetuzumab, Teclistamab, Glofitamab, Epcoritamab, Talquetamab, Ivonescimab, Cadonilimab, Tarlatamab, Zenocutuzumab, and Catumaxomab, have achieved notable success in clinical trials. This review highlights clinically approved BsAbs and provides a comprehensive summary of their therapeutic applications in cancer treatment.

Beyond inherently killing cancer cells by directly inducing double-strand DNA breaks, local radiotherapy (RT) can exert immune-priming effects and reprogram the tumor microenvironment (TME) from immune-cold tumors into inflamed, or "hot" tumors. Nevertheless, this immunogenic antitumor response may be partially counterbalanced by the upregulation of vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-β) induced by RT. Y332D, a bispecific antibody that simultaneously blockades VEGF and TGF-β, effectively synergized with RT, leading to a durable antitumor effect. Mechanistically, Y332D counteracted negative RT effects that are attributed to the upregulation of TGF-β and VEGF-mediated epithelial-mesenchymal transition, extracellular matrix remodeling, aberrant angiogenesis, immunosuppression, and radioresistance, as well as further enhanced or complemented the positive effects of RT, such as cGAS-STING activation, immunogenic cell death, enhanced antigen presentation, increased T cell infiltration, and antiangiogenic effects, thereby reprograming the TME from immune "cold" to inflamed state and forming an effective in-situ vaccine that, beyond local tumor eradication, could potentiate antitumor immune response and regress preestablished abscopal metastases. Together, our results indicate that this combination strategy successfully overcame the negative effects caused by RT and augmented abscopal effects, extending the application of RT to the treatment of both local and metastatic disease.

Despite the success of immune checkpoint inhibitors (ICIs) in multiple malignant tumors, a significant proportion of patients remain unresponsive to treatment. Radiotherapy (RT) elicits immunogenic antitumor responses but concurrently activates several immune evasion mechanisms. Our earlier research demonstrated the efficacy of YM101, an anti-TGF-β/PD-L1 bispecific antibody, in stroma-rich tumors. Nevertheless, YM101 has demonstrated reduced effectiveness in non-inflamed tumors characterized by poor immune cell infiltration. This study investigated the potential synergy between RT and YM101 in overcoming immunotherapy resistance and mitigating RT-induced pulmonary fibrosis. The antitumor activity and survival outcomes of RT plus YM101 treatment in vivo were explored in several non-inflamed murine tumor models. Furthermore, the inhibition of pulmonary metastases was assessed in a pulmonary metastasis model. The impact of RT on dendritic cell (DC) maturation was quantified by flow cytometry, whereas cytokine and chemokine secretions were measured by ELISA. To comprehensively characterize changes in the tumor microenvironment, we utilized a combination of methods, including flow cytometry, IHC staining, multiplex inmunofluorecence and RNA sequencing. Additionally, we evaluated the impact of YM101 on RT-induced pulmonary fibrosis. RT plus YM101 significantly inhibited tumor growth, prolonged survival and inhibited pulmonary metastases compared with monotherapies in non-inflamed tumors with poor immune infiltration. RT promoted DC maturation in a dose-dependent manner and increased the secretions of multiple proinflammatory cytokines. Mechanistically, RT plus YM101 simultaneously increased the infiltration and activation of intratumoral DCs and tumor-infiltrating lymphocytes and reshaped the tumor microenvironment landscape. Notably, YM101 attenuated both RT-induced peritumoral fibrosis and pulmonary fibrosis. Our findings suggest that RT combined with YM101 enhances antitumor immunity and overcomes resistance in non-inflamed tumors in preclinical models, while simultaneously showing potential in mitigating RT-induced fibrosis. This combination therapy demonstrates promise in overcoming ICI resistance, while potentially sparing normal pulmonary tissue, thereby providing a strong rationale for further clinical investigations.

Cancer remains a formidable global health challenge, necessitating innovative therapeutic approaches to enhance treatment efficacy and reduce adverse effects. The traditional Chinese medicine (TCM), as an embodiment of ancient wisdom, has been validated to regulate the holistic human capacity against both internal and external "evils" in accordance with TCM principles. Therefore, it stands to reason to integrate TCM into current cancer therapy paradigms, such as chemotherapy, immunotherapy, and targeted therapy. This strategy conceptually intends to circumvent the inevitable side effects derived from present treatment, alleviate the discomfort, mollify the detrimental mood and synergize tumoricidal effects of distinct approaches. However, it is still vague whether TCM exert favorable function in cancer treatment. Therefore, it is imperative to retrieve and compile the existing literature on TCM in the realm of cancer, followed by a comprehensive recapitulation and synthesis of its core findings. Recently, with the advancement of contemporary biologic and medical theory and technology, it has become both feasible and imperative to elucidate the molecular signaling mechanisms and cellular biology underlying TCM. Specifically, leveraging TCM pharmaceutic components can not only directly impact tumor biology at the molecular level, but regulate the tumor immune environment through distinct pathways. Additionally, the administration of external TCM treatments such as acupuncture and moxibustion also demonstrates beneficial effects in cancer patients. Through comprehensive analysis, we demonstrated that TCM not only potentially increases the efficacy of conventional cancer treatments, but also significantly mitigates their toxic side effects, thereby prolonging patients' prognosis and improving their living quality. Furthermore, we have underscored the challenges and prospects associated with the integration of TCM into contemporary oncological practices, placing particular emphasis on the imperative for rigorous clinical trials and molecular investigations to substantiate the efficacy and safety of these combined therapeutic approaches. This synthesis aims to pave the way for a more integrated approach to cancer treatment rooted in both traditional wisdom and cutting-edge science.

Female-specific cancers, particularly breast, cervical, ovarian, and uterine cancers, account for nearly 40

An up-to-date comprehensive assessment of the cancer burden attributable to risk factors is essential for cancer prevention. We analyzed the population attributable fraction (PAF) of cancer disability-adjusted life years (DALYs) attributable to 11 level 2 risk factors using data from the Global Burden and Disease Study (GBD) 2019. We highlighted that almost half of the cancer DALYs can be preventable by modifying relevant risk factors. The attributable cancer DALYs increased by 60.42%-105.0 million from 1990 to 2019. Tobacco, dietary risks, alcohol use, high body-mass index, and air pollution were the top five risk factors. The PAFs attributable to high fasting plasma glucose, high body-mass index, and low physical activity have increased worldwide from 1990 to 2019. Unsafe sex was the leading risk factor for women before age of 54. Tailored prevention programs targeted at specific populations should be scaled up to reduce the cancer burden in the future.

This paper develops a two-sector growth model incorporating the state-owned and private-owned sectors and introduces biased subsidies and credit discrimination to explore how the effects of these two important policy distortions differ and interact. Based on the calibration of the Chinese economy, our primary findings are as follows. (1) Subsidy policies favoring state-owned enterprises improve the efficiency of resource allocation within each sector, whereas credit policies discriminating against private-owned enterprises reduce the efficiency of resource allocation within each sector. (2) Although both biased subsidies and credit discrimination lead to resource misallocation between sectors and ultimately harm total factor productivity (TFP), biased subsidies have a greater impact on intersectoral resource misallocation, limiting the TFP gains from mitigating credit discrimination. The policy implication is that mitigating distortions caused by biased subsidies should be prioritized over mitigating distortions caused by credit discrimination.

Immunotherapy, particularly with immune checkpoint inhibitors, has significantly transformed cancer treatment. Despite its success, many patients struggle to respond adequately or sustain long-lasting clinical improvement. A growing consensus has emerged that radiotherapy (RT) enhances the response rate and overall efficacy of immunotherapy. Although combining RT and immunotherapy has been extensively investigated in preclinical models and has shown promising results, establishing itself as a dynamic and thriving area of research, clinical evidence for this combination strategy over the past five years has shown both positive and disappointing results, suggesting the need for a more nuanced understanding. This review provides a balanced and updated analysis of the combination of immunotherapy and RT. We summarized the preclinical mechanisms through which RT boosts antitumor immune responses and mainly focused on the outcomes of recently updated clinical trials, including those that may not have met expectations. We investigated the optimization of the therapeutic potential of this combined strategy, including key challenges, such as fractionation and scheduling, lymph node irradiation, and toxicity. Finally, we offered insights into the prospects and challenges associated with the clinical translation of this combination therapy, providing a realistic perspective on the current state of research and potential future directions.

Cytokines are critical in regulating immune responses and cellular behavior, playing dual roles in both normal physiology and the pathology of diseases such as cancer. These molecules, including interleukins, interferons, tumor necrosis factors, chemokines, and growth factors like TGF-β, VEGF, and EGF, can promote or inhibit tumor growth, influence the tumor microenvironment, and impact the efficacy of cancer treatments. Recent advances in targeting these pathways have shown promising therapeutic potential, offering new strategies to modulate the immune system, inhibit tumor progression, and overcome resistance to conventional therapies. In this review, we summarized the current understanding and therapeutic implications of targeting cytokine and chemokine signaling pathways in cancer. By exploring the roles of these molecules in tumor biology and the immune response, we highlighted the development of novel therapeutic agents aimed at modulating these pathways to combat cancer. The review elaborated on the dual nature of cytokines as both promoters and suppressors of tumorigenesis, depending on the context, and discussed the challenges and opportunities this presents for therapeutic intervention. We also examined the latest advancements in targeted therapies, including monoclonal antibodies, bispecific antibodies, receptor inhibitors, fusion proteins, engineered cytokine variants, and their impact on tumor growth, metastasis, and the tumor microenvironment. Additionally, we evaluated the potential of combining these targeted therapies with other treatment modalities to overcome resistance and improve patient outcomes. Besides, we also focused on the ongoing research and clinical trials that are pivotal in advancing our understanding and application of cytokine- and chemokine-targeted therapies for cancer patients.

Background Recently, therapeutic antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1) have exerted potent anticancer effect in a variety of tumors. However, blocking the PD-1/PD-L1 axis alone is not sufficient to restore normal immune response. Other negative regulators of antitumor immunity, like TGF-β and VEGFA, are also involved in immune escape of tumor cells and induce immunotherapy resistance. Methods We developed a novel anti-TGF-β/VEGF bispecific antibody Y332D based on the Nano-YBODY™ technology platform. The CCK-8, flow cytometry, SBE4 luciferase reporter assay, western blotting and transwell assays were used to measure the biological activities of the anti-TGF-β moiety. The NFAT luciferase reporter assay, luminescent cell viability assay and tube formation assay were used to measure the biological activities of the anti-VEGF moiety. The in vivo anticancer efficacy of Y332D alone or in combination with PD-1 blockade was evaluated in H22, EMT-6, 4T1, and AKT/Ras-driven murine hepatocellular carcinoma tumor models. Immunofluorescent staining, flow cytometry, RNA-seq and quantitative RT-PCR were adopted to analyze the alterations in the tumor microenvironment. Results Y332D could maintain specific binding affinities for TGF-β and VEGFA. Y332D almost entirely counteracted the in vitro biological functions of TGF-β and VEGFA, including immunosuppression, activated TGF-β signaling, epithelial-mesenchymal transition (EMT), activated VEGF/VEGFR signaling, HUVEC proliferation and tube formation. The in vivo experiment data demonstrated that Y332D was more effective in inhibiting tumor growth and metastasis than anti-TGF-β and anti-VEGF monotherapies. In combination therapies, Y332D plus PD-1 blockade exhibited the most potent and durable anticancer effect. Mechanistically, Y332D plus PD-1 blockade upregulated the density and function of tumor-infiltrating lymphocytes and exerted reinvigorated antitumor immunity. Conclusion Y332D could simultaneously block TGF-β and VEGF signalings. In comparison with the monotherapies, Y332D combined with PD-1 blockade exerts superior antitumor effect through improving immune microenvironment.